JPS62221623A - Gallstone dissolvent - Google Patents

Abstract

PURPOSE:A gallstone dissolvent, containing a farnesylacetic acid ester as an active ingredient, having improved gallstone dissolving action with slight toxicity and side effect and continuously usable for a long period. CONSTITUTION:A gallstone dissolvent containing a compound expressed by the formula (R is 1-10C alkyl or 2-10C alkenyl) as an active ingredient. The clinical dose of the compound expressed by the formula is normally 10-500mg/ day (oral), preferably 20-100mg/day (oral) and dividedly administered (2-3 times). The compound expressed by the formula is readily obtained by reacting, e.g. nerolidol (3,7,11-trimethyl-1,6,10-dodecatrien-3-ol) with an orthoacetic acid ester expressed by the formula CH3C(OR)3.

Description

[Detailed description of the invention] [Industrial application field] The invention relates to a gallstone dissolving agent.

[Conventional technology]

Conventionally, chenodeoxycholic acid and ursodeoxycholic acid in bile components have been clinically used as therapeutic agents for cholesterol cholelithiasis. Furthermore, it has been reported that monooctanoyl obtained by esterifying the α-hydroxyl group of α-limonene and glycerin with octanoic acid has a significantly stronger ability to dissolve gallstones than the cholic acids mentioned above (Igi
mi et al., Dig.

Dis, 21,926 (1976) and Th1stl
e et al., Gastroenterolog) r+ 72.
1141 (1927)].

[Problem that the invention seeks to solve]

Clinically used chenodeoxycholic acid and ursodeoxycholic acid have low ability and rate of dissolving cholesterol gallstones, and are not sufficiently effective as gallstone dissolving agents. Furthermore, α-limonene and monooctanoin have not been used clinically because they cause side effects such as vomiting, diarrhea, and abdominal pain.

Therefore, an object of the present invention is to provide a gallstone dissolving agent that has excellent gallstone dissolving action, has little toxicity and side effects, and can be used for a long period of time.

[Means for solving problems]

According to the invention, the above object is achieved by the general formula % (1) in which R represents an alkyl group having 1 to 10 carbon atoms or an alkenyl group having 2 to 10 carbon atoms. This is achieved by providing a gallstone dissolving agent containing farnesyl acetate as an active ingredient.

Examples of the alkyl group having 1 to 10 carbon atoms represented by R in general formula (1) include methyl group, ethyl group,
Examples include propyl group, butyl group, pentyl group, octyl group, decyl group, etc.Alkenyl groups having 2 to 10 carbon atoms include vinyl group, allyl group, frenyl group (3-methyl-2-butenyl group) ), geranyl group (3,
7-dimethyl-2,6-octagenyl group) and the like.

A representative example of farnesyl acetate represented by general formula (1) is methyl farnesyl acetate (hereinafter referred to as FA
(hereinafter referred to as FAG) and farnesylgeranyl acetate (hereinafter referred to as FAG).

The 7-arnesyl acetate represented by the general formula (1) is a known compound, for example, unrolidol (3゜7.11-
trimethyl-1,6,10-dodecatrien-3-ol) in the presence of an acidic catalyst to form orthoacetic acid represented by the general formula % (in the formula, R is as shown in the above table). In addition, the 7-arnesyl acetate represented by the general formula (1) can be easily produced by reacting with an ester. Similarly to general esters, the 7-arnesyl acetate can be used by transesterification reaction to convert its alcohol residue into other 0 that can be substituted with an alcohol residue (see Japanese Patent Publication No. 56-23415) Representative examples of farnesyl acetate represented by general formula (1) and monooctanoin (below).

Test Example 1 Test using a stationary disk (1) Preparation of a disk of cholesterol monohydrate Cholesterol (manufactured by Kanto Kagaku Co., Ltd., special grade) 5F A 95% bath solution of ethanol (manufactured by Kanto Kagaku Co., Ltd., special grade) 40
Cholesterol monohydrate was obtained by dissolving it in 0m at 60°C and crystallizing it at room temperature for 48 hours.It was confirmed that the obtained crystals were monohydrate using a digital trace moisture measuring device ( The cholesterol monohydrate obtained in this way (
Hereinafter, this will be abbreviated as chM) 100"P of microcrystals is accurately weighed, placed in a pellet having a concave portion with a diameter of 1.3 cIgl, and degassed using an IR tablet forming device. Pressure molded for 20 minutes at a pressure of /-, ch
M disk was obtained (90(2)), and a cross-sectional view of the testing device is shown in Figure 1. 1... motor,
2... Stirrer, 3... Sample inlet/outlet, 4...
Nitrogen gas supply port, 5゛°・Test compound, 6°°・chM
Disc, 7...Bellet.

(8) Test method and test results A pellet 7 holding a chM disk 6 formed by the static disk method was fixed to the bottom of the test device.

Pour the liquid substance 5 of the test compound from the sample inlet/outlet 3,
National induction motor 8GH5M as 0 motor stirring with stirrer 2 connected to motor 1
(Matsushita'FM, manufactured by Kisangyo Co., Ltd.) using the National Speed Controller 1) V-103-IA
(Matsushita Electric Industrial Co., Ltd.) to adjust the rotational speed of the stirrer to i 50 r, p, m.

Inside the test equipment is Ricoh Thermo Stan) UH15AE
(Riko Kagaku Sangyo Co., Ltd.*) to maintain the temperature at 37°C, and flow nitrous gas from the nitrogen gas supply port 4 to prevent air oxidation of the test liquid.

After the start of the test, 0.02 jlj is sampled using a microsyringe (manufactured by Kusano Kagaku Kikai Seisakusho Co., Ltd.) at regular intervals, and the amount of dissolved chM is determined by an enzymatic method. Using the enzyme reagent Sanassay F-CHO (Sanko Junyaku Co., Ltd.!A) for measuring free cholesterol as an enzymatic coloring reagent, the absorbance at the maximum absorption wavelength of 555 nm of the purple quinone pigment produced by the enzymatic reaction was measured using a spectrophotometer. The amount of chM dissolved is quantitatively analyzed by measuring with UV-120-02 (Shimadzu Corporation Exhibition).

The reaction mechanism of Sun Assay F-CHO is shown in FIG. 100η in the Sun Assay F-CHO kit as a standard solution.
The following formula shows a method for calculating O chMi dissolution using a cholesterol standard solution of /ctl and a blind solution in which 0.02 d of solvent is added to the coloring reagent 3 me.

C= (Is/Estd)
I) C: Concentration of chM Es: Absorbance of test compound Estd: 100+v/dl wvy<fo-'
Absorbance of lA quasi-solution Next, the initial dissolution rate of chM ch at the initial stage of Kl dissolution
It is defined as the value obtained by dividing the time change dC/dt of the M concentration C by the effective surface area S of the chM disk.

The chM dissolution fC in the test compound was investigated over time based on formula (II), and the *
The time change dc/dt of degree C was determined, and then the initial dissolution rate K was calculated based on formula (1).The results are shown in Table 1. Table 1: Table 1: Table 1: Margins Test Example 2: Experimental cholelithiasis improvement effect Test (1) Composition of test animals and groups Male ddK mice purchased from Kitayama Lapes Co., Ltd.
(5 weeks old, around 232 cm) were preliminarily reared for one week, and healthy ones were used for the test.

Animals fed synthetic feed at the time of use (weight at time of use: 29.
2 to 34.59) were randomly assigned to 8 animals per group, and the following 4 groups were established.

Blank group: normal feed (Oriental yeast, MF) fed group Control group: fed synthetic feed (Oriental yeast, specified combination), intragallbladder administration of 10 μt of 5 w/w % lecithin saline solution FAG administration group: synthetic feed (Oriental yeast, specified formulation), 5 w/w% lecithin added FAG, 10
μt intragallbladder administration group FAM administration group: reared on synthetic feed (Oriental yeast, specified formulation), fed with 5 w/w% lecithin-added FAM, 10
Intra-gallbladder administered μt mice were reared at a constant temperature and humidity of 23±1° C. and humidity of 50±5%, and were given the above-mentioned feed and tap water ad libitum. Furthermore, the experiment was conducted in the same room.

(2) Preparation of sample solution 5w/w each for FAG and FAM of the test compound
% of lecithin, thoroughly dissolved with an ultrasonicator, and then 10μt of it was added to a microsyringe (
The solution was administered into the gallbladder of mice with cholelithiasis using Oμt1 (manufactured by Hamilton, Inc.). In addition, conlecithin (egg S) was used for biochemical use manufactured by Wako Pure Chemical Industries, Ltd., and physiological saline solution for injection was used manufactured by Otsuka Pharmaceutical Co., Ltd.

(8) Preparation of synthetic feed A synthetic powder feed having the composition shown below was prepared by Oriental Yeast Co., Ltd. When feeding, add 30 liters of distilled water at the time of use, thoroughly knead and shape, and after 9 minutes,
It was dried and solidified at 65°C for 5 hours. Note that the number in parentheses is the component.

Cholesterol (1,6), sodium cholate (0,
6), putter (12,0), casein (22,2), sucrose (11,1), cellulose (6,0), mineral (4
,5), vitamins (1,5), cornstarch (28,
5), α-starch (7,5), linoleic oil (4,5), mineral content (1), q in parentheses: potassium (70,0
), phosphorus (165,0), calcium (93,0), sodium (41,7), magnesium (12,5), iron (4,5), zinc (0,85), manganese (0,37)
, copper (0,095), iodine (0,08') vitamin 1?
Medium content, () inner cape: A (500 IU), 1h (1,2
), B2(4,0), Ba(1,a), Btz(0
,0005), C(30,0), D3(100IU),
E (5,0), K3 (5,2), biotin (0,02)
, folic acid (0,2), calcium pantothenate (5,0'
l, para-aminobenzoin [(5, (1, niacin (6,
0), inositol (6,0), choline chloride (200)
(4) Test method and judgment Based on the method of Deatsu et al., a synthetic feed was prepared and mice were caused to develop cholesterol-based gallstones. i.e. 50 animals
The blank group consisted of animals that were fed synthetic feed naturally and reared for the same period of time on normal feed. Starting from the third week of rearing on synthetic feed, we opened the abdomen of three animals every three days, observed the presence or absence of any gallstones in the gallbladder, and confirmed the onset of cholelithiasis [Jyoji Deatsu et al., Japanese Pharmacological Journal, 82.171-180 (1983)].

At the 4th week, the abdomen was opened under light pendoparbital anesthesia, and 8 animals found to have developed gallstones were randomly divided into a control group, FAG administration group, and FAM administration group, and 10 μl of the sample solution was administered to each group. It was administered into the gallbladder and the abdomen was closed.

Three hours after administering the sample solution, the animals were sacrificed by cervical dislocation, the bile duct was immediately ligated, and the gallbladder was removed. The presence or absence of gallstones in the removed gallbladder was determined according to the following criteria, and a significant difference test was performed using the U-test.

(5) Test results By feeding synthetic samples containing cholesterol and sodium cholate for 4 weeks, mice developed cholesterol-based gallstones, and 10μe each of the samples F'AG and FAM were directly administered into the gallbladder. The gallstone dissolving effect was investigated.

In Table 2, the degree of intrabiliary gallstone formation in each group is indicated by - to ox based on the criteria, and the results of a significant difference test with the control group by U-test are also shown.

Margin below 2nd table blank - 5ooo
-Control lO intragallbladder 0026 -FA
G 10 Intragallbladder 0 2 4 2
2.0831FAM 10 In the gallbladder 0
1 4 3 1.9721 No gallstone formation was observed in the gallbladder in the blank group fed normal feed, but gallstone formation was observed on the gold side in the synthetic feed group, so animals were randomly divided into groups of 8. , sample solution 5 each 10μΔ
Three hours after the abdomen was closed, the abdomen was opened again and observed. As shown in Table 2, in the control group there were 2 cases of Ten and 6 cases of Ox, and in the FAG administration group. There were 2 cases of earth, 4 cases of 10, and 2 cases of ox, and in the FAM administration group, 1 case of shi, 4 cases of +, and 3 cases of masu.
A significant difference between the control group and the control group was tested using the - test, and it was found that the FAG administration group and the FAM administration group had a significant difference (0,0
1<P<0.05') Gallstone dissolving effect was observed.

As is clear from Tables 1 and 2, all of the test compounds were found to have the ability to dissolve cholesterol-based gallstones.

As described above, farnesyl acetate represented by the general formula (1) has excellent properties as a gallstone dissolving agent, and was further confirmed to have low toxicity in toxicity tests. For example, the acute toxicity value (LDso (mouse oral and rat oral)) of FAG was 9 f/positive or higher.

From the above results, farnesyl acetate represented by general formula (1) can be used as a gallstone dissolving agent.

The clinical dose of nystere farnesyl acetate represented by general formula (I) is generally 10 to 500 μ/day (oral),
The best dose is 20 to 100 per day (oral).
It is divided into 2 to 3 doses by divided administration.

Farnesyl acetate of general formula (I) can be prepared for administration using any conventional R-cutting method. Therefore, the present invention also includes a pharmaceutical composition containing at least one farnesyl acetate represented by the general formula (1), which is suitable as a human medicine. Such compositions are provided for use in a conventional manner with any required pharmaceutical carriers or excipients.

Desirably, the composition is provided in a form suitable for absorption from the gastrointestinal tract. Tablets and capsules for oral administration are in unit dosage form, binders such as syrup, acacia, gelatin, sorbitol, tracanth, polyvinylpyrrolidone, etc.; excipients such as lactose, corn starch, calcium phosphate, sorbitol, etc. lubricants such as magnesium stearate, Merck, polyethylene glycol, silica, etc.; disintegrants such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. You can leave it there. Tablets may be coated by methods well known in the art. Oral liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, etc.
Alternatively, it may be a dry product that is redissolved in water or other suitable vehicle before use. Such liquid formulations may contain commonly used excipients, such as suspending agents, such as norbit syrup, methylcellulose, glucose/
Sugar syrups, gelatin hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats, etc.; emulsifiers, such as lecithin, rubitan monooleate, gum arabic, etc.; non-aqueous vehicles, such as almond oil, fractionated coconut oil, oily esters, propylene glycol, ethyl alcohol, etc.; preservatives, such as methyl p-hydroxybenzoate, p-
- May contain propyl hydroxybenzoate, norbic acid, etc.

〔Example〕

The present invention will be specifically explained below using examples. Although examples of formulations containing FAG as an active ingredient are shown as actual examples, the present invention is not limited to these examples.

F A G 2!
M'corn starch 552 carboxycellulose lsr polyvinylpyrrolidone 3v total amount
10 (1) 14 tablets each weighing 100q were prepared by a conventional method. Each tablet contains 25'9 of FAG.

Example 2 Powder and Capsule Both powders of F' A G 25P were mixed to prepare a powder. Further, this powder was filled into No. 3 hard capsules to prepare capsules.

〔Effect of the invention〕

The gallstone dissolving agent containing farnesyl acetate represented by the general formula (1) as an active ingredient is provided by the present invention.

[Brief explanation of drawings]

FIG. 1 shows a sectional view of an apparatus for performing a gallstone dissolution test using the stationary disk method, and FIG. 2 shows the reaction mechanism of Sun Assay F-CHO, a reagent for measuring free cholesterol. DESCRIPTION OF SYMBOLS 1... Motor, 2... Stirrer, 3... Sample inlet/outlet, 4... Nitrogen gas supply port, 5... Test compound, 6... chM disk, 7... Pent.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents an alkyl group having 1 to 10 carbon atoms or an alkenyl group having 2 to 10 carbon atoms. ) A gallstone dissolving agent containing farnesyl acetate as an active ingredient.